Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation
- Conditions
- Chronic Obstructive Pulmonary Disease
- Interventions
- Drug: Inhaled CorticosteroidDrug: Inhaled Long-Acting Beta AgonistDrug: Inhaled Long-Acting Muscarinic AntagonistDrug: Placebo
- Registration Number
- NCT04456673
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
To evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate or severe Chronic Obstructive Pulmonary Disease (COPD) as measured by
* Annualized rate of acute moderate or severe COPD exacerbation (AECOPD)
Secondary Objectives:
To evaluate the effect of dupilumab administered every 2 weeks on
* Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to placebo
* Health related quality of life, assessed by the change from baseline to Week 52 in the St. George's Respiratory Questionnaire (SGRQ)
* Pre-bronchodilator FEV1 over 52 weeks compared to placebo
* Lung function assessments
* Moderate and severe COPD exacerbations
* To evaluate safety and tolerability
* To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA)
- Detailed Description
Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and 12 weeks of follow-up
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 935
-
Participants with a physician diagnosis of COPD who met the following criteria at screening:
- Current or former smokers with a smoking history of ≥10 pack-years.
- Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ratio <0.70 and post-bronchodilator FEV1 % predicted >30% and ≤70%).
- Medical Research Council (MRC) Dyspnea Scale grade ≥2.
- Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough.
- Documented history of high exacerbation risk defined as exacerbation history of ≥2 moderate or ≥1 severe within the year prior to inclusion. At least one exacerbation should have occurred while the participant was taking inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate exacerbations were recorded by the investigator and defined as AECOPD that required either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations had to require the use of systemic corticosteroids. Severe exacerbations were recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
- Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥1 month prior to Visit 1; Double therapy (LABA + LAMA) allowed if ICS is contraindicated.
-
Evidence of Type 2 inflammation: Participants with blood eosinophils ≥300 cells/microliter at Visit 1.
- COPD diagnosis for less than 12 months prior to randomization.
- Participants with current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma.
- Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome etc) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
- Cor pulmonale, evidence of right cardiac failure.
- Long-term treatment with oxygen >4.0 L/min OR if a participant requires more than 2.0 L/min in order to maintain oxygen saturation >88%
- Hypercapnia requiring Bi-level ventilation.
- AECOPD as defined in inclusion criteria within 4 weeks prior to screening, or during the screening period.
- Respiratory tract infection within 4 weeks prior to screening, or during the screening period.
- History of, or planned pneumonectomy or lung volume reduction surgery. Participants who were participating in the acute phase of a pulmonary rehabilitation program, ie, who started rehabilitation <4 weeks prior to screening (Note: participants in the maintenance phase of a rehabilitation program can be included).
- Diagnosis of α-1 anti-trypsin deficiency.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dupilumab Dupilumab SAR231893 Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks Dupilumab Inhaled Corticosteroid Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks Dupilumab Inhaled Long-Acting Beta Agonist Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks Dupilumab Inhaled Long-Acting Muscarinic Antagonist Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks Placebo Inhaled Corticosteroid Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks Placebo Inhaled Long-Acting Beta Agonist Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks Placebo Inhaled Long-Acting Muscarinic Antagonist Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks Placebo Placebo Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks
- Primary Outcome Measures
Name Time Method Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-week Treatment Period Baseline (Day 1) to Week 52 Moderate exacerbations were recorded by the Investigator and defined as acute exacerbation of COPD (AECOPD) event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were also recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period.
- Secondary Outcome Measures
Name Time Method Annualized Rate of Severe Chronic Obstructive Pulmonary Disease Exacerbations Over the 52-week Treatment Period Baseline (Day 1) to Week 52 Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period.
Change From Baseline in Forced Expiratory Flow (FEF) 25 to 75 Percent (%) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52 Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 44 and 52 FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the FEF at 25% to 75% of forced vital capacity (FVC), where FVC was defined as the volume of air that can be forcibly blown out after full inspiration in the upright position. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) to Week 12 Baseline (Day 1) and Week 12 The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score to Week 52 Baseline (Day 1) and Week 52 The SGRQ is a 50-item self-administered questionnaire designed to measure and quantify health status in adult participants with chronic airflow limitation and rated on electronic diary. Scores by dimension were calculated for 3 domains: symptoms (respiratory symptoms: frequency and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response had a unique empirically derived weight where lowest possible weight was 0 and the highest was 100. Total score was obtained by summing all positive responses in the questionnaire. The total score and domain score was derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating worse health status/health related quality of life. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Percentage of Participants With Saint George's Respiratory Questionnaire Improvement ≥4 Points at Week 52 Baseline (Day 1) and Week 52 A responder was defined as a participant with improvement from baseline in SGRQ total score at Week 52 by ≥4 points. Percentage of participants who achieved a clinically meaningful response in SGRQ total score (improvement by ≥4 points)/responders are reported. SGRQ is a 50-item self-administered questionnaire. Scores by dimension were calculated for 3 domains: symptoms (respiratory symptoms: frequency and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response had unique empirically derived weight where lowest possible weight was 0 and highest was 100. Total score was obtained by summing all positive responses in questionnaire. Total score and domain score was derived from relevant items and converted to a score of 0 to 100; higher score indicating worse health status/health related quality of life.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Week 52 Baseline (Day 1) and Week 52 The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 24, 36, and 44 Baseline (Day 1) and Weeks 2, 4, 8, 24, 36 and 44 The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 12, 24, 36, and 52 Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36 and 52 The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 referred to the spirometry performed consistent with the mechanism of action of reliever (30 minutes for albuterol or another short-acting beta agonists). Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease Exacerbation Event During the 52-week Treatment Period Baseline (Day 1) and up to Weeks 12, 24, 36 and 52 The time to first moderate or severe exacerbation was defined as date of the first event minus randomization date +1. Moderate exacerbations were recorded by the Investigator and defined as AECOPD event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Median time as well as 95% confidence interval was calculated using Kaplan-Meier estimates.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days An AE was defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed or worsened or became serious during TE period (between the first administration of study treatment to the last administration of the study treatment + 98 days).
Percentage of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Hematology From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days Blood samples were collected to determine PCSA in hematology. PCSA values were defined as abnormal values considered medically important by the Sponsor according to pre-defined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests. Criteria for PCSA: Hemoglobin (Hb): ≤115 grams per liter (g/L) (Male\[M\]); ≤95 g/L (Female\[F\]), ≥185 g/L (M); ≥165 g/L (F), Decrease from baseline ≥20 g/L; Hematocrit: ≤0.37 volume per volume (v/v) (M); ≤0.32 v/v (F), ≥0.55 v/v (M); ≥0.5 v/v (F); Erythrocyte Count: ≥6 Tera/L; Platelet count: \<100 Giga/L, ≥700 Giga/L; Leukocytes: \<3 Giga/L (Non-Black \[NB\]); \<2 Giga/L (Black \[B\]), ≥16 Giga/L; Neutrophils: \<1.5 Giga/L (NB); \<1 Giga/L (B); Lymphocytes: \>4 Giga/L; Monocytes: \>0.7 Giga/L; Basophils: \>0.1 Giga/L; Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN ≥0.5 Giga/L).
Percentage of Participants With Potentially Clinically Significant Abnormalities in Clinical Chemistry From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days Blood samples were collected to determine PCSA in chemistry. PCSA criteria: Sodium: ≤129 millimoles (mmol)/L, ≥160 mmol/L; Potassium: \<3 mmol/L, ≥5.5 mmol/L; Chloride: \<80 mmol/L, \>115 mmol/L; Glucose: ≤3.9 mmol/L and \<lower limit of normal (LLN), ≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted);Total cholesterol: ≥7.74 mmol/L; Creatinine kinase: \>3 ULN, \>10 ULN; Creatinine: ≥150 micromoles (µmol)/L (adults), ≥30% change from baseline, ≥100% change from baseline, Creatinine Clearance (CG): ≥60 - \<90 milliliter per minute (mL/min), ≥30 - \<60 mL/min, ≥15 - \<30 mL/min, \<15 mL/min; Urea nitrogen: ≥17 mmol/L; Uric acid: \<120 μmol/L, \>408 μmol/L; Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST): \>3 ULN, \>5 ULN, \>10 ULN; Alkaline phosphatase (ALP): \>1.5 ULN; Total bilirubin (TB): \>1.5 ULN, \>2 ULN; ALT and TB: ALT \>3 ULN and Bilirubin \> 2 ULN; Direct bilirubin (DB) and TB: DB \>35% Bilirubin and Bilirubin \>1.5 ULN; Albumin: ≤25 g/L.
Percentage of Participants With Abnormal Results for Urine Protein in Urinalysis Baseline (Day 1), Weeks 4, 8, 12, 24, 36, 52 and 64 Urine dipstick samples were collected to determine the significant abnormalities in urine protein.
Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab Up to Week 52 Plasma samples were collected to evaluate antibodies to dupilumab. Pre-existing immunoreactivity is defined as an ADA positive response in the assay at baseline with all post-treatment ADA results negative, or an ADA positive response at baseline with all post-treatment ADA responses less than 4-fold over baseline titer levels. Treatment-emergent response is defined as a positive response in the ADA assay post first dose, when baseline results are negative or missing. Treatment-boosted response is defined as an ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over baseline titer levels, when baseline results are positive.
Trial Locations
- Locations (334)
Radiance Clinical Research Site Number : 8400029
🇺🇸Lampasas, Texas, United States
Cullman Research Center, LLC Site Number : 8400095
🇺🇸Cullman, Alabama, United States
Pulmonary & Sleep Associates of Jasper PC Site Number : 8400090
🇺🇸Jasper, Alabama, United States
Scottsboro Quick Care Clinic Site Number : 8400116
🇺🇸Scottsboro, Alabama, United States
Phoenix Medical Group Site Number : 8400061
🇺🇸Peoria, Arizona, United States
Medical Advancement Center of Arizona Site Number : 8400107
🇺🇸Tempe, Arizona, United States
Asthma and Allergy Institute Site Number : 8400022
🇺🇸Little Rock, Arkansas, United States
Kern Research, Inc Site Number : 8400031
🇺🇸Bakersfield, California, United States
NewportNativeMD, Inc Site Number : 8400032
🇺🇸Newport Beach, California, United States
Prospective Research Innovations, Inc. Site Number : 8400063
🇺🇸Rancho Cucamonga, California, United States
ACRC Studies Site Number : 8400094
🇺🇸San Diego, California, United States
Institute of HealthCare Assessment, Inc. Site Number : 8400015
🇺🇸San Diego, California, United States
Allianz Research Institute Site Number : 8400007
🇺🇸Westminster, California, United States
Innovative Clinical Research Site Number : 8400018
🇺🇸Lafayette, Colorado, United States
Helix Biomedics, LLC Site Number : 8400035
🇺🇸Boynton Beach, Florida, United States
Pioneer Clinical Research Site Number : 8400043
🇺🇸Boynton Beach, Florida, United States
Renaissance Research and Medical Group, Inc Site Number : 8400092
🇺🇸Cape Coral, Florida, United States
St. Francis Sleep, Allergy and Lung Institute Site Number : 8400020
🇺🇸Clearwater, Florida, United States
Beautiful Minds Clinical Research Center Site Number : 8400081
🇺🇸Cutler Bay, Florida, United States
Omega Research Consultants, LLC Site Number : 8400021
🇺🇸DeBary, Florida, United States
Sciences Connections, LLC Site Number : 8400133
🇺🇸Doral, Florida, United States
InvesClinic, LLC Site Number : 8400039
🇺🇸Fort Lauderdale, Florida, United States
Finlay Medical Research Site Number : 8400071
🇺🇸Greenacres City, Florida, United States
Direct Helpers Medical Center Inc Site Number : 8400079
🇺🇸Hialeah, Florida, United States
DL Research Solutions Inc Site Number : 8400089
🇺🇸Miami, Florida, United States
Phoenix Medical Research, LLC Site Number : 8400012
🇺🇸Miami, Florida, United States
Columbus Clinical Services Site Number : 8400062
🇺🇸Miami, Florida, United States
Reed Medical Research Site Number : 8400123
🇺🇸Miami, Florida, United States
De La Cruz Research Center, LLC Site Number : 8400075
🇺🇸Miami, Florida, United States
Florida Institute for Clinical Research Site Number : 8400129
🇺🇸Orlando, Florida, United States
Central Florida Pulmonary Group, PA Site Number : 8400101
🇺🇸Orlando, Florida, United States
Innovation Medical Research Center Site Number : 8400114
🇺🇸Palmetto Bay, Florida, United States
Family Medical Specialists of Florida, PA Site Number : 8400077
🇺🇸Plant City, Florida, United States
Coastal Pulmonary And Critical Care Site Number : 8400013
🇺🇸Saint Petersburg, Florida, United States
Florida Pulmonary Research Center Site Number : 8400001
🇺🇸Winter Park, Florida, United States
Appalachian Clinical Research Site Number : 8400048
🇺🇸Adairsville, Georgia, United States
Northlake Medical Group Site Number : 8400099
🇺🇸Atlanta, Georgia, United States
River Birch Research, LLC Site Number : 8400045
🇺🇸Blue Ridge, Georgia, United States
Medical Centre of Conyers Site Number : 8400064
🇺🇸Conyers, Georgia, United States
David Kavtaradze MD, Inc. Site Number : 8400135
🇺🇸Cordele, Georgia, United States
Gwinnett Biomedical Research Site Number : 8400052
🇺🇸Lawrenceville, Georgia, United States
Southeast Lung Associates Site Number : 8400003
🇺🇸Rincon, Georgia, United States
Herman Clinical Research LLC Site Number : 8400078
🇺🇸Suwanee, Georgia, United States
Avant Research Associates LLC Site Number : 8400118
🇺🇸Crowley, Louisiana, United States
Genesis Clinical Research & Consulting Site Number : 8400050
🇺🇸Fall River, Massachusetts, United States
Infinity Medical Research Site Number : 8400004
🇺🇸South Dartmouth, Massachusetts, United States
Henry Ford Health System Site Number : 8400053
🇺🇸Detroit, Michigan, United States
Revive Research Institute Site Number : 8400120
🇺🇸Lathrup Village, Michigan, United States
Romedica, LLC Site Number : 8400034
🇺🇸Rochester, Michigan, United States
Covenant Healthcare Site Number : 8400057
🇺🇸Saginaw, Michigan, United States
Great Lakes Research Institute Site Number : 8400096
🇺🇸Southfield, Michigan, United States
Montana Medical Research Site Number : 8400019
🇺🇸Missoula, Montana, United States
Somnos Clinical Research Site Number : 8400016
🇺🇸Lincoln, Nebraska, United States
Quality Clinical Research, Inc. Site Number : 8400073
🇺🇸Omaha, Nebraska, United States
Jersey City Breathing Center Site Number : 8400137
🇺🇸Jersey City, New Jersey, United States
WellNow Urgent Care Site Number : 8400132
🇺🇸E. Amherst, New York, United States
Northwell Health Site Number : 8400054
🇺🇸New Hyde Park, New York, United States
Mid Hudson Medical Research PLLC Site Number : 8400037
🇺🇸New Windsor, New York, United States
Great Lakes Medical Research Site Number : 8400044
🇺🇸Westfield, New York, United States
Onsite Clinical Solutions LLC Site Number : 8400042
🇺🇸Charlotte, North Carolina, United States
Clinical Research of Gastonia Site Number : 8400010
🇺🇸Gastonia, North Carolina, United States
Monroe Biomedical Research Site Number : 8400087
🇺🇸Monroe, North Carolina, United States
Lake Norman Pulmonary and Sleep Medicine - Mooresville Site Number : 8400006
🇺🇸Mooresville, North Carolina, United States
Lapis Clinical Research At BlueSkies Family Medicine Site Number : 8400117
🇺🇸Mooresville, North Carolina, United States
Coastal Carolina Health Care, P.A. Site Number : 8400025
🇺🇸New Bern, North Carolina, United States
Southeastern Research Center Site Number : 8400068
🇺🇸Winston-Salem, North Carolina, United States
Optimed Research, LTD Site Number : 8400082
🇺🇸Columbus, Ohio, United States
Toledo Institute of Clinical Research Site Number : 8400024
🇺🇸Toledo, Ohio, United States
Allergy, Asthma and Clinical Research Center Site Number : 8400127
🇺🇸Oklahoma City, Oklahoma, United States
Clinical Research of Central PA Site Number : 8400009
🇺🇸DuBois, Pennsylvania, United States
Frontier Clinical Research, LLC Site Number : 8400049
🇺🇸Scottdale, Pennsylvania, United States
Carolina Medical Research, LLC Site Number : 8400026
🇺🇸Clinton, South Carolina, United States
MD First Research Site Number : 8400105
🇺🇸Lancaster, South Carolina, United States
LLM Research Site Number : 8400125
🇺🇸Myrtle Beach, South Carolina, United States
Health Concepts Site Number : 8400027
🇺🇸Rapid City, South Dakota, United States
Pulmonary & Sleep Specialists Site Number : 8400136
🇺🇸Dickson, Tennessee, United States
Clinical Trials Center of Middle Tennessee Site Number : 8400066
🇺🇸Franklin, Tennessee, United States
MultiSpecialty Clinical Research Site Number : 8400110
🇺🇸Johnson City, Tennessee, United States
REX Clinical Trials Site Number : 8400143
🇺🇸Beaumont, Texas, United States
Clinrx Research Site Number : 8400059
🇺🇸Carrollton, Texas, United States
Houston Pulmonary and Sleep Associates Site Number : 8400011
🇺🇸Cypress, Texas, United States
Biopharma Informatic - Cardiff Avenue - PPDS Site Number : 8400055
🇺🇸Houston, Texas, United States
Prolato Clinical Research Center Site Number : 8400128
🇺🇸Houston, Texas, United States
Pioneer Research Solutions, Inc. Site Number : 8400070
🇺🇸Houston, Texas, United States
DCOL Center for Clinical Research Site Number : 8400028
🇺🇸Longview, Texas, United States
Metroplex Pulmonary and Sleep Center Site Number : 8400131
🇺🇸McKinney, Texas, United States
Clinrx Research, LLC Site Number : 8400069
🇺🇸Plano, Texas, United States
Diagnostics Research Group Site Number : 8400038
🇺🇸San Antonio, Texas, United States
Mt. Olympus Medical Research Site Number : 8400115
🇺🇸Sugar Land, Texas, United States
Pulmonary Research of Abingdon, LLC Site Number : 8400030
🇺🇸Abingdon, Virginia, United States
Clinical Research Partners Site Number : 8400040
🇺🇸Richmond, Virginia, United States
Allergy, Asthma & Sinus Center, S.C. Site Number : 8400088
🇺🇸Greenfield, Wisconsin, United States
Investigational Site Number : 0320007
🇦🇷Berazategui, Buenos Aires, Argentina
Investigational Site Number : 0320006
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number : 0320004
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number : 0320001
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number : 0320003
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number : 0320010
🇦🇷La Plata, Buenos Aires, Argentina
Investigational Site Number : 0320013
🇦🇷Lobos, Buenos Aires, Argentina
Investigational Site Number : 0320005
🇦🇷Quilmes, Ciudad De Buenos Aires, Argentina
Investigational Site Number : 0320011
🇦🇷Cordoba, Córdoba, Argentina
Investigational Site Number : 0320008
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320009
🇦🇷Rosario, Santa Fe, Argentina
Investigational Site Number : 0320002
🇦🇷Buenos Aires, Argentina
Investigational Site Number : 0320012
🇦🇷Launs Este, Argentina
Investigational Site Number : 0360008
🇦🇺Kent Town, South Australia, Australia
Investigational Site Number : 0360005
🇦🇺Clayton, Victoria, Australia
Investigational Site Number : 0360001
🇦🇺Spearwood, Western Australia, Australia
Investigational Site Number : 0560002
🇧🇪Edegem, Belgium
Investigational Site Number : 0560001
🇧🇪Leuven, Belgium
Investigational Site Number : 0560003
🇧🇪Liege, Belgium
Investigational Site Number : 0560004
🇧🇪Mechelen, Belgium
SER da Bahia Site Number : 0760019
🇧🇷Salvador, Bahia, Brazil
CEDOES - Centro de Diagnostico e Pesquisa de Osteoporose do ES Site Number : 0760020
🇧🇷Vitoria, Espírito Santo, Brazil
Instituto Mederi de Pesquisa e Saude Site Number : 0760008
🇧🇷Passo Fundo, Rio Grande Do Sul, Brazil
Irmandade da Santa Casa de Misericordia de Porto Alegre Site Number : 0760017
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Sao Lucas Site Number : 0760001
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
HOSPITAL DIA DO PULMAO Site Number : 0760006
🇧🇷Blumenau, Santa Catarina, Brazil
UFSC - Hospital Universitário Site Number : 0760018
🇧🇷Florianópolis, Santa Catarina, Brazil
PUC Campinas - Sociedade Campineira de Educaçao e Instruçao Site Number : 0760015
🇧🇷Campinas, São Paulo, Brazil
FUNDACAO DO ABC - FACULDADE DE MEDICINA DO ABC (FMABC) Site Number : 0760007
🇧🇷Santo Andre, São Paulo, Brazil
CPQuali Pesquisa Clinica Site Number : 0760003
🇧🇷Sao Paulo, São Paulo, Brazil
Instituto de Pesquisa Grupo NotreDame Intermedica Site Number : 0760012
🇧🇷Sao Paulo, São Paulo, Brazil
Nucleo de Pesquisa Clinica e Ensino da Rede Sao Camilo Site Number : 0760021
🇧🇷Sao Paulo, São Paulo, Brazil
InCor - Instituto do Coraçao do Hospital das Clinicas da FMUSP Site Number : 0760002
🇧🇷Sao Paulo, São Paulo, Brazil
Clinica de Alergia Martti Antila Site Number : 0760009
🇧🇷Sorocaba, São Paulo, Brazil
Investigational Site Number : 1005025
🇧🇬Burgas, Bulgaria
Investigational Site Number : 1005021
🇧🇬Dupnitsa, Bulgaria
Investigational Site Number : 1005012
🇧🇬Haskovo, Bulgaria
Investigational Site Number : 1005011
🇧🇬Montana, Bulgaria
Investigational Site Number : 1005008
🇧🇬Plovdiv, Bulgaria
Investigational Site Number : 1005015
🇧🇬Ruse, Bulgaria
Investigational Site Number : 1005013
🇧🇬Ruse, Bulgaria
Investigational Site Number : 1005018
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005003
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005001
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005006
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005002
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005026
🇧🇬Sofia, Bulgaria
Investigational Site Number : 1005024
🇧🇬Stara Zagora, Bulgaria
Investigational Site Number : 1005004
🇧🇬Stara Zagora, Bulgaria
Investigational Site Number : 1005023
🇧🇬Veliko Tyrnovo, Bulgaria
Investigational Site Number : 1005027
🇧🇬Veliko Tyrnovo, Bulgaria
Investigational Site Number : 1005019
🇧🇬Vidin, Bulgaria
Investigational Site Number : 1005020
🇧🇬Vratsa, Bulgaria
Investigational Site Number : 1240015
🇨🇦Calgary, Alberta, Canada
Investigational Site Number : 1240018
🇨🇦Kamloops, British Columbia, Canada
Investigational Site Number : 1240017
🇨🇦Kelowna, British Columbia, Canada
Investigational Site Number : 1240014
🇨🇦Moncton, New Brunswick, Canada
Investigational Site Number : 1240010
🇨🇦Ajax, Ontario, Canada
Investigational Site Number : 1240009
🇨🇦Sarnia, Ontario, Canada
Investigational Site Number : 1240007
🇨🇦Windsor, Ontario, Canada
Investigational Site Number : 1240004
🇨🇦Montreal, Quebec, Canada
Investigational Site Number : 1240012
🇨🇦Québec, Quebec, Canada
Investigational Site Number : 1240001
🇨🇦Quebec, Canada
Investigational Site Number : 1240005
🇨🇦Quebec, Canada
Investigational Site Number : 1520009
🇨🇱Valdivia, Los Ríos, Chile
Investigational Site Number : 1520006
🇨🇱Curicó, Maule, Chile
Investigational Site Number : 1520001
🇨🇱Talca, Maule, Chile
Investigational Site Number : 1520007
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520003
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520002
🇨🇱Santiago, Reg Metropolitana De Santiago, Chile
Investigational Site Number : 1520004
🇨🇱Quillota, Valparaíso, Chile
Investigational Site Number : 1700002
🇨🇴Bogota, Colombia
Investigational Site Number : 1700007
🇨🇴Bucaramanga, Colombia
Investigational Site Number : 1700005
🇨🇴Manizales, Colombia
Investigational Site Number : 2030009
🇨🇿Havlickuv Brod, Czechia
Investigational Site Number : 2030004
🇨🇿Jihlava, Czechia
Investigational Site Number : 2030001
🇨🇿Jindrichuv Hradec III, Czechia
Investigational Site Number : 2030007
🇨🇿Kralupy nad Vltavou, Czechia
Investigational Site Number : 2030003
🇨🇿Miroslav, Czechia
Investigational Site Number : 2030010
🇨🇿Nymburk, Czechia
Investigational Site Number : 2030002
🇨🇿Strakonice, Czechia
Investigational Site Number : 2500009
🇫🇷Bayonne, France
Investigational Site Number : 2500002
🇫🇷Dijon, France
Investigational Site Number : 2500005
🇫🇷Lyon, France
Investigational Site Number : 2500003
🇫🇷Montpellier, France
Investigational Site Number : 2500007
🇫🇷Paris, France
Investigational Site Number : 2500008
🇫🇷Paris, France
Investigational Site Number : 2500006
🇫🇷Pessac, France
Investigational Site Number : 2500001
🇫🇷Saint Herblain, France
Investigational Site Number : 2760024
🇩🇪Berlin, Germany
Investigational Site Number : 2760025
🇩🇪Berlin, Germany
Investigational Site Number : 2760017
🇩🇪Darmstadt, Germany
Investigational Site Number : 2760009
🇩🇪Frankfurt am Main, Germany
Investigational Site Number : 2760002
🇩🇪Hamburg, Germany
Investigational Site Number : 2760003
🇩🇪Hannover, Germany
Investigational Site Number : 2760007
🇩🇪Koblenz, Germany
Investigational Site Number : 2760023
🇩🇪Leipzig, Germany
Investigational Site Number : 2760011
🇩🇪Leipzig, Germany
Investigational Site Number : 2760010
🇩🇪Lübeck, Germany
Investigational Site Number : 2760012
🇩🇪Mainz, Germany
Investigational Site Number : 2760008
🇩🇪Marburg, Germany
Investigational Site Number : 2760020
🇩🇪Peine, Germany
Investigational Site Number : 2760016
🇩🇪Rosenheim, Germany
Investigational Site Number : 2760018
🇩🇪Wiesbaden, Germany
Investigational Site Number : 3000006
🇬🇷Athens, Greece
Investigational Site Number : 3000001
🇬🇷Athens, Greece
Investigational Site Number : 3000003
🇬🇷Heraklion, Greece
Investigational Site Number : 3000002
🇬🇷Ioannina, Greece
Investigational Site Number : 3000007
🇬🇷Palaio Faliro, Athens, Greece
Investigational Site Number : 3000004
🇬🇷Thessaloniki, Greece
Investigational Site Number : 3480003
🇭🇺Edelény, Hungary
Investigational Site Number : 3480004
🇭🇺Gödöllö, Hungary
Investigational Site Number : 3480002
🇭🇺Hajdunánás, Hungary
Investigational Site Number : 3480006
🇭🇺Mosonmagyaróvár, Hungary
Investigational Site Number : 3480005
🇭🇺Szombathely, Hungary
Investigational Site Number : 3480001
🇭🇺Százhalombatta, Hungary
Investigational Site Number : 4280008
🇱🇻Balvi, Latvia
Investigational Site Number : 4280007
🇱🇻Rezekne, Latvia
Investigational Site Number : 4280001
🇱🇻Riga, Latvia
Investigational Site Number : 4280005
🇱🇻Riga, Latvia
Investigational Site Number : 4280006
🇱🇻Riga, Latvia
Investigational Site Number : 4280002
🇱🇻Riga, Latvia
Investigational Site Number : 4280003
🇱🇻Riga, Latvia
Investigational Site Number : 4400001
🇱🇹Kaunas, Lithuania
Investigational Site Number : 4400003
🇱🇹Kaunas, Lithuania
Investigational Site Number : 4400008
🇱🇹Kaunas, Lithuania
Investigational Site Number : 4400007
🇱🇹Klaipeda, Lithuania
Investigational Site Number : 4400005
🇱🇹Vilnius, Lithuania
Investigational Site Number : 4840008
🇲🇽Benito Juarez, Ciudad De Mexico, Mexico
Investigational Site Number : 4840002
🇲🇽Guadalajara, Jalisco, Mexico
Investigational Site Number : 4840013
🇲🇽Guadalajara, Jalisco, Mexico
Investigational Site Number : 4840011
🇲🇽Zapopan, Jalisco, Mexico
Investigational Site Number : 4840004
🇲🇽Monterrey, Nuevo León, Mexico
Investigational Site Number : 4840003
🇲🇽Monterrey, Nuevo León, Mexico
Investigational Site Number : 4840010
🇲🇽Chihuahua, Mexico
Investigational Site Number : 4840006
🇲🇽Durango, Mexico
Investigational Site Number : 4840007
🇲🇽Mexico City, Mexico
Investigational Site Number : 4840009
🇲🇽Mexico City, Mexico
Investigational Site Number : 4840005
🇲🇽Veracruz, Mexico
Investigational Site Number : 5280005
🇳🇱Arnhem, Netherlands
Investigational Site Number : 5280001
🇳🇱Breda, Netherlands
Investigational Site Number : 5280010
🇳🇱Dordrecht, Netherlands
Investigational Site Number : 5280009
🇳🇱Harderwijk, Netherlands
Investigational Site Number : 5280002
🇳🇱Leeuwarden, Netherlands
Investigational Site Number : 5280006
🇳🇱Nijmegen, Netherlands
Investigational Site Number : 5280011
🇳🇱Roermond, Netherlands
Investigational Site Number : 5280008
🇳🇱Zutphen, Netherlands
Investigational Site Number : 5280004
🇳🇱Zwolle, Netherlands
Investigational Site Number : 6040002
🇵🇪Lima Lima, Peru
Investigational Site Number : 6040006
🇵🇪Lima, Peru
Investigational Site Number : 6040004
🇵🇪Lima, Peru
Investigational Site Number : 6040001
🇵🇪Lima, Peru
Investigational Site Number : 6040005
🇵🇪Piura, Peru
Investigational Site Number : 6160009
🇵🇱Grudziadz, Kujawsko-pomorskie, Poland
Investigational Site Number : 6160007
🇵🇱Krakow, Malopolskie, Poland
Investigational Site Number : 6160015
🇵🇱Grodzisk Mazowiecki, Mazowieckie, Poland
Investigational Site Number : 6160010
🇵🇱Rzeszow, Podkarpackie, Poland
Investigational Site Number : 6160008
🇵🇱Bialystok, Podlaskie, Poland
Investigational Site Number : 6160018
🇵🇱Katowice, Slaskie, Poland
Investigational Site Number : 6160011
🇵🇱Katowice, Slaskie, Poland
Investigational Site Number : 6160022
🇵🇱Ostrowiec Swietokrzyski, Swietokrzyskie, Poland
Investigational Site Number : 6160014
🇵🇱Elblag, Warminsko-mazurskie, Poland
Investigational Site Number : 6160019
🇵🇱Krakow, Poland
Investigational Site Number : 6160020
🇵🇱Nowa Sol, Poland
Investigational Site Number : 6200007
🇵🇹Almada, Portugal
Investigational Site Number : 6200006
🇵🇹Aveiro, Portugal
Investigational Site Number : 6200002
🇵🇹Guimarães, Portugal
Investigational Site Number : 6200009
🇵🇹Lisboa, Portugal
Investigational Site Number : 6200012
🇵🇹Matosinhos, Portugal
Investigational Site Number : 6425004
🇷🇴Bacau, Romania
Investigational Site Number : 6425003
🇷🇴Cluj-Napoca, Romania
Investigational Site Number : 6425005
🇷🇴Constanta, Romania
Investigational Site Number : 6425002
🇷🇴Iasi, Romania
Investigational Site Number : 6425006
🇷🇴Pitesti, Romania
Investigational Site Number : 6425001
🇷🇴Timisoara, Romania
Investigational Site Number : 6430001
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430003
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430002
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430009
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number : 6430010
🇷🇺Ryazan, Russian Federation
Investigational Site Number : 6430013
🇷🇺Saint Petersburg, Russian Federation
Investigational Site Number : 6430014
🇷🇺Saint Petersburg, Russian Federation
Investigational Site Number : 6430004
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number : 6430012
🇷🇺Stavropol, Russian Federation
Investigational Site Number : 6430006
🇷🇺Tomsk, Russian Federation
Investigational Site Number : 6430008
🇷🇺Ulyanovsk, Russian Federation
Investigational Site Number : 6430005
🇷🇺Voronezh, Russian Federation
Investigational Site Number : 6880005
🇷🇸Belgrade, Serbia
Investigational Site Number : 6880006
🇷🇸Belgrade, Serbia
Investigational Site Number : 6880007
🇷🇸Belgrade, Serbia
Investigational Site Number : 6880003
🇷🇸Kragujevac, Serbia
Investigational Site Number : 6880001
🇷🇸Sremska Kamenica, Serbia
Investigational Site Number : 6880002
🇷🇸Valjevo, Serbia
Investigational Site Number : 7030007
🇸🇰Banska Bystrica, Slovakia
Investigational Site Number : 7030006
🇸🇰Humenne, Slovakia
Investigational Site Number : 7030005
🇸🇰Kosice, Slovakia
Investigational Site Number : 7030003
🇸🇰Levice, Slovakia
Investigational Site Number : 7030001
🇸🇰Poprad, Slovakia
Investigational Site Number : 7030002
🇸🇰Spisska Nova Ves, Slovakia
Investigational Site Number : 7100015
🇿🇦Benoni, South Africa
Investigational Site Number : 7100004
🇿🇦Cape Town, South Africa
Investigational Site Number : 7100014
🇿🇦Chatsworth, South Africa
Investigational Site Number : 7100001
🇿🇦Durban, South Africa
Investigational Site Number : 7100013
🇿🇦Durban, South Africa
Investigational Site Number : 7100003
🇿🇦Durban, South Africa
Investigational Site Number : 7100010
🇿🇦Durban, South Africa
Investigational Site Number : 7100002
🇿🇦Gatesville, South Africa
Investigational Site Number : 7100011
🇿🇦Gauteng, South Africa
Investigational Site Number : 7100009
🇿🇦Johannesburg, South Africa
Investigational Site Number : 7100012
🇿🇦Middelburg, South Africa
Investigational Site Number : 7100006
🇿🇦Parow, South Africa
Investigational Site Number : 7100005
🇿🇦Pretoria, South Africa
Investigational Site Number : 7100008
🇿🇦Somerset West, South Africa
Investigational Site Number : 7240007
🇪🇸Oviedo, Asturias, Spain
Investigational Site Number : 7240002
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 7240009
🇪🇸Badalona, Catalunya [Cataluña], Spain
Investigational Site Number : 7240012
🇪🇸Caceres, Cáceres, Spain
Investigational Site Number : 7240003
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number : 7240008
🇪🇸Valencia, Valenciana, Comunidad, Spain
Investigational Site Number : 7240010
🇪🇸Málaga, Spain
Investigational Site Number : 7240011
🇪🇸Zaragoza, Spain
Investigational Site Number : 8040011
🇺🇦Chernivtsi, Ukraine
Investigational Site Number : 8040002
🇺🇦Ivano-Frankivsk, Ukraine
Investigational Site Number : 8040003
🇺🇦Ivano-Frankivsk, Ukraine
Investigational Site Number : 8040001
🇺🇦Kharkiv, Ukraine
Investigational Site Number : 8040007
🇺🇦Kyiv, Ukraine
Investigational Site Number : 8040004
🇺🇦Kyiv, Ukraine
Investigational Site Number : 8040006
🇺🇦Lviv, Ukraine
Investigational Site Number : 8040010
🇺🇦Ternopil, Ukraine
Investigational Site Number : 8040008
🇺🇦Zaporizhzhia, Ukraine
Investigational Site Number : 8040009
🇺🇦Zaporizhzhya, Ukraine
Investigational Site Number : 8260003
🇬🇧Cambridge, Cambridgeshire, United Kingdom
Investigational Site Number : 8260002
🇬🇧Blackpool, Lancashire, United Kingdom
Investigational Site Number : 8260006
🇬🇧Swansea, Neath Port Talbot, United Kingdom
Investigational Site Number : 8260007
🇬🇧North Shields, Newcastle Upon Tyne, United Kingdom
Investigational Site Number : 8260004
🇬🇧South Shields, Newcastle Upon Tyne, United Kingdom
Investigational Site Number : 8260013
🇬🇧Nottingham, Nottinghamshire, United Kingdom
Investigational Site Number : 8260012
🇬🇧Aylesbury, United Kingdom
Investigational Site Number : 8260001
🇬🇧Bradford, United Kingdom
Investigational Site Number : 8260005
🇬🇧Bristol, United Kingdom
Investigational Site Number : 8260011
🇬🇧Chippenham, United Kingdom
Investigational Site Number : 8260015
🇬🇧Derby, United Kingdom